Dynamic Metabolomics Atlas of Radiation-induced Liver Injury and Hepatocyte Proliferation Process in Rat.

Abstract

This study aims to elucidate the processes involved in radiation-induced liver injury and subsequent hepatocyte proliferation, and to identify novel metabolic profiles associated with progression of liver injury and hepatocyte proliferation. Six-week-old male Sprague-Dawley rats were exposed to a single 25 Gy dose of radiation to the whole liver to induce a model of radiation-induced liver injury and subsequent hepatocyte proliferation. Liver injury and hepatocyte proliferation were assessed using a range of techniques, including Masson's trichrome staining, liver histopathology, ELISA, immunohistochemistry, and Western blotting. Dynamic changes in metabolic profiles and biomarker concentrations in liver tissue were investigated using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry. After radiation exposure, acute radiation-induced liver dysfunction occurs, but then there is gradual recovery over time, concomitant with the onset of hepatocyte proliferation. Metabolomic analysis of liver tissues at different time points, specifically day 1, day 8, day 15, and day 30 postirradiation, revealed notable differences in all 22 metabolites, with a predominance of lipid metabolites. Among them, 9 metabolites showed more than a twofold change on days 15 and 30. We validated the correlation between these 9 metabolites with injury scores and Ki-67 positive cells (%). Notably, there was a strong negative correlation between glycerylphosphorylethanolamine (GPE) and the injury score (correlation coefficient: -0.701) and between 1-hexadecanoyl-2-(5-hydroxy-8-oxo-6E-octenoyl)-sn-glycero-3-phosphoserine (PHOOA-PS) and the Ki-67 positive cells (%) (correlation coefficient: -0.824). Additionally, GPE has significant value in differentiating the degree of injury [area under the curve (AUC) = 0.958]. This study successfully established a rat model of radiation-induced hepatic injury and subsequent hepatocyte proliferation, shedding light on dynamic metabolic changes at different times.